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![m Dnase2a gene expression analysis in E14.5 Klf1 wild-type and mutant mice fetal liver. (A) Semiquantitative radioactive time course PCR assay of Dnase2a cDNA from E14.5 fetal liver wild-type ( ϩ / ϩ ) and KO ( Ϫ / Ϫ ) Klf1 embryos. The mDnase2a and the  -actin reverse primers were end-labeled with [ ␥ - 32 P]ATP. The 220-bp mDnase2a and the 260-bp  -actin PCR fragments analyzed at 28 and 30 PCR cycles are shown. (B) Northern hybridization assay of E14.5 wild-type ( ϩ / ϩ ) and KO ( Ϫ / Ϫ ) fetal liver RNA using mKlf1 , mDnase2a , or  -actin cDNAs as probes. (C) Relative expression levels of m Dnase2a in E14.5 Klf1 -null ( Ϫ / Ϫ ) fetal livers compared with those of the wild-type ( ϩ / ϩ ) littermates. Levels were quantified by RT-qPCR, and results are expressed as the value relative to the 18S rRNA. *** , P Ͻ 0.001 according to a t test.](profile/Paolo-Moi/publication/51539099/figure/fig1/AS:277252475506689@1443113549099/m-Dnase2a-gene-expression-analysis-in-E145-Klf1-wild-type-and-mutant-mice-fetal-liver.png)
m Dnase2a gene expression analysis in E14.5 Klf1 wild-type and mutant mice fetal liver. (A) Semiquantitative radioactive time course PCR assay of Dnase2a cDNA from E14.5 fetal liver wild-type ( ϩ / ϩ ) and KO ( Ϫ / Ϫ ) Klf1 embryos. The mDnase2a and the  -actin reverse primers were end-labeled with [ ␥ - 32 P]ATP. The 220-bp mDnase2a and the 260-bp  -actin PCR fragments analyzed at 28 and 30 PCR cycles are shown. (B) Northern hybridization assay of E14.5 wild-type ( ϩ / ϩ ) and KO ( Ϫ / Ϫ ) fetal liver RNA using mKlf1 , mDnase2a , or  -actin cDNAs as probes. (C) Relative expression levels of m Dnase2a in E14.5 Klf1 -null ( Ϫ / Ϫ ) fetal livers compared with those of the wild-type ( ϩ / ϩ ) littermates. Levels were quantified by RT-qPCR, and results are expressed as the value relative to the 18S rRNA. *** , P Ͻ 0.001 according to a t test.
Source publication
A key regulatory gene in definitive erythropoiesis is the erythroid Kruppel-like factor (Eklf or Klf1). Klf1 knockout (KO) mice die in utero due to severe anemia, while residual circulating red blood cells retain their nuclei. Dnase2a is another critical gene in definitive erythropoiesis. Dnase2a KO mice are also affected by severe anemia and die i...
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Context 1
... whether the mouse Dnase2a is Klf1 dependent, we first examined the expression level of Dnase2a in fetal liver cells from E14.5 Klf1-null mice compared to that from wt littermates. Semiquantitative RT-PCR showed a significant de- crease in Dnase2a gene expression in the Klf1-null fetal liver cells compared to that in cells with the wt genotype (Fig. 1A). Northern blot analysis (Fig. 1B) performed on wt and Klf1-null 4146 PORCU ET AL. MOL. CELL. ...
Context 2
... dependent, we first examined the expression level of Dnase2a in fetal liver cells from E14.5 Klf1-null mice compared to that from wt littermates. Semiquantitative RT-PCR showed a significant de- crease in Dnase2a gene expression in the Klf1-null fetal liver cells compared to that in cells with the wt genotype (Fig. 1A). Northern blot analysis (Fig. 1B) performed on wt and Klf1-null 4146 PORCU ET AL. MOL. CELL. ...
Context 3
... cDNA as probes revealed the absence, as expected, of Klf1 mRNA and only trace amounts of Dnase2a mRNA with respect to the -actin used as a control. Further support for Dnase2a depen- dency on Klf1 was provided by RT-qPCR analysis performed on wt and Klf1-null E14.5 fetal liver mRNAs. The expression level of Dnase2a mRNA was dramatically reduced (Fig. 1C) in the Klf1-null fetal liver compared to that in wt littermates (SD, 0.11; P, 0.00014). No significant difference between the wt and the heterozygous littermates was detected. We next assayed extracts from E14.5 wt, heterozygous, and Klf1-null fetal liver cells for DNase II-alpha enzymatic activity. We tested both time course ...
Context 4
... confirm the presence of Klf1 in fetal liver macrophages, E13.5 wt mouse fetal liver cells were double stained for Klf1 and F4/80 antibody. Figure 4D shows in a single field both positive and negative cells for Klf1 and/or F4/80 (representing the positive and negative controls, respectively). All cells in the field are Hoechst positive (Fig. 4D, panel 1). A great fraction of the cells is Klf1 positive (see left arrow, Fig. 4D, panel 2); most of them are erythroid cells, while others are macro- phages (right arrow, Fig. 4D, panel 2), as indicated by the ...
Similar publications
A key regulatory gene in definitive erythropoiesis is the transcription factor Krüppel-like factor 1 (Klf1). Klf1 null mice die in utero by day 15.5 (E15.5) due to impaired definitive erythropoiesis and severe anemia. Definitive erythropoiesis takes place in erythroblastic islands in mammals. Erythroblastic islands are formed by a central macrophag...
Citations
... During hematopoiesis its levels are highest in the common myeloid and megakaryocyte/erythroid progenitors, after which it remains elevated only in the erythroid cell (14, 15). Additional studies demonstrate EKLF is also expressed in the unique central macrophage cell of the erythroblastic island (16)(17)(18)(19)(20). ...
... Using E13.5 fetal liver cells as our source we find that CRE is expressed in the F4/80+ cell population ( Figure 4A); however, as seen in earlier studies, not all cells are positive, but rather 39 ± 3% are, which matches that previously seen by marked GFP+ (36% (17)). These results, using an independent approach from those used previously (16)(17)(18)(19)(20), provide additional support for EKLF's expression in the F4/80+ central macrophage of the erythroblastic island. ...
Introduction: EKLF/Klf1 is a tissue-restricted transcription factor that plays a critical role in all aspects of erythropoiesis. Of particular note is its tissue-restricted pattern of expression, a property that could prove useful for expression control of a linked marker or enzymatic gene. Methods and results: With this in mind, we fused the CRE recombinase to the genomic EKLF coding region and established mouse lines. We find by FACS analyses that CRE expression driven by the EKLF transcription unit recapitulates erythroid-restricted expression with high penetrance in developing embryos. We then used this line to test its properties in the adult, where we found EKLF/CRE is an active and is a robust mimic of normal EKLF expression in the adult bone marrow. EKLF/CRE is also expressed in erythroblastic island macrophage in the fetal liver, and we demonstrate for the first time that, as seen during embryonic development, EKLF is also expressed in adult BM-derived erythroblastic island macrophage. Our data also support lineage studies showing EKLF expression at early stages of hematopoiesis. Discussion: The EKLF/CRE mouse lines are novel reagents whose availability will be of great utility for future experiments by investigators in the red cell field. KEYWORDS CRE/LoxP, EKLF/KLF1, fetal liver, bone marrow, erythroid cells, macrophage cells Highlights • Mice with CRE expression under the control of the EKLF promoter have been established.
... The functional role of EBI was first suggested by Mohandas and colleague, who showed that in hyper-transfused rats, the numbers of EBI in the bone marrow were significantly decreased (Mohandas and Prenant, 1978). The importance of the central macrophage in supporting normal erythropoiesis was further supported by the abnormal macrophage differentiation in EMP-null (Wei et al., 2019;Soni et al., 2006), KLF1-null (Mukherjee et al., 2021;Porcu et al., 2011), and other mouse models (Chow et al., 2013;Sadahira et al., 1995;Kawane et al., 2001;Mankelow et al., 2004), leading to significantly impaired erythropoiesis and anemia. Furthermore, the depletion of macrophages with either clodronate liposomes or CD169-diptheria toxin leading to impaired erythropoiesis provide direct evidence that macrophages play critical roles in supporting erythropoiesis in vivo, particularly during stress erythropoiesis (Chow et al., 2013;Ramos et al., 2013). ...
Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large amounts of iron in order to generate hemoglobin and ultimately undergo enucleation to become mature red blood cells, ultimately delivering oxygen in the circulation. Thus, erythropoiesis is a finely tuned, multifaceted process requiring numerous properly timed physiological events to maintain efficient production of 2 million red blood cells per second in steady state. Iron is required for normal functioning in all human cells, the erythropoietic compartment consuming the majority in light of the high iron requirements for hemoglobin synthesis. Recent evidence regarding the crosstalk between erythropoiesis and iron metabolism sheds light on the regulation of iron availability by erythroblasts and the consequences of insufficient as well as excess iron on erythroid lineage proliferation and differentiation. In addition, significant progress has been made in our understanding of dysregulated iron metabolism in various congenital and acquired malignant and non-malignant diseases. Finally, we report several actual as well as theoretical opportunities for translating the recently acquired robust mechanistic understanding of iron metabolism regulation to improve management of patients with disordered erythropoiesis, such as anemia of chronic inflammation, β-thalassemia, polycythemia vera, and myelodysplastic syndromes.
... 6 Normal EBI macrophages stimulate erythropoiesis, maturation, and enucleation. [7][8][9][10][11][12] However, changes to EBI central macrophages in cases of MM and their effects on erythroid development remain unknown. In this study, we examined the clinical characteristics and associated risk factors for anemia in 202 patients with NDMM, as well as the differences between erythroblasts in non-anemic and anemic patients. ...
Objective
To examine the clinical characteristics and anemia-related factors in patients with newly diagnosed multiple myeloma (NDMM), as well as the effect and mechanism of erythroblastic islands (EBIs) and EBI macrophages in NDMM patients with anemia.
Methods
We collected and analyzed clinical data to find anemia-related factors. Using flow cytometry, the numbers and ratios of erythroblasts and EBI macrophages were determined. RNA sequencing (RNA-seq) was used to determine the differences of EBI macrophages in NDMM patients with or without anemia.
Results
Based on the clinical characteristics of NDMM patients with anemia, MCV, abnormal levels of albumin, osteolytic lesions, and Durie-Salmon (DS) stage are risk factors for anemia. Patients with anemia have fewer erythroblasts, erythroblastic islands (EBIs), and EBI macrophages in their bone marrow than patients without anemia. RNA-seq analysis of EBI macrophages from the bone marrow of patients with and without anemia revealed that macrophages from patients with anemia are impaired and tend to promote the production of interleukin-6, which has been demonstrated to be an essential survival factor of myeloma cells and protects them from apoptosis.
Conclusion
In NDMM patients with anemia, EBI macrophages are impaired, which causes anemia in those patients. Our finding highlights the significance of EBI macrophages in anemia in NDMM patients and provides a new strategy for recovery from anemia in these patients.
... It is responsible for up-regulation of DNase II and the expression of VCAM-1, CD163, CD169, enabling the macrophage to promote erythroid development [109][110][111]. In the absence of KLF1 expression, mice have reduced DNase II and die of severe anemia [112,113]. KLF1 also regulates the expression of IL-33, which is a cytokine that promotes the maturation of RBCs [111]. Additionally, IL-33 differentiates monocytes into macrophages involved in erythrophagocytosis and iron recycling [114] and has been shown to be elevated in SCD patients [115]. ...
Sickle cell disease (SCD) is an inherited blood disorder caused by a β-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events leading to multiple complications, such as hemolytic anemia, vaso-occlusion, chronic inflammation, and tissue damage. Macrophages participate in extravascular hemolysis by removing damaged RBCs, hence preventing the release of free hemoglobin and heme, and triggering inflammation. Upon erythrophagocytosis, macrophages metabolize RBC-derived hemoglobin, activating mechanisms responsible for recycling iron, which is then used for the generation of new RBCs to try to compensate for anemia. In the bone marrow, macrophages can create specialized niches, known as erythroblastic islands (EBIs), which regulate erythropoiesis. Anemia and inflammation present in SCD may trigger mechanisms of stress erythropoiesis, intensifying RBC generation by expanding the number of EBIs in the bone marrow and creating new ones in extramedullary sites. In the current review, we discuss the distinct mechanisms that could induce stress erythropoiesis in SCD, potentially shifting the macrophage phenotype to an inflammatory profile, and changing their supporting role necessary for the proliferation and differentiation of erythroid cells in the disease. The knowledge of the soluble factors, cell surface and intracellular molecules expressed by EBI macrophages that contribute to begin and end the RBC’s lifespan, as well as the understanding of their signaling pathways in SCD, may reveal potential targets to control the pathophysiology of the disease.
... The expression of Klf1 on macrophages was first highlighted in human primary cells, and its involvement in the regulation of IL12-p40 expression was also demonstrated [59]. Subsequently, a further demonstration of both the expression and activity of Klf1 in central macrophages of erythroblastic islands was described in vivo [28,37]. Recently, a Klf1+ F4/80+ macrophage population in murine foetal liver cells with a peculiar pattern of expression was identified. ...
... The absence of Klf1 affects another essential role of macrophages in the erythroid niches, which con-sists of the engulfment of extruded nuclei and their subsequent degradation in lysosomes ( Figure 1D). Fundamental to this function is the expression of DnaseII-alpha protein in macrophages, which hydrolyses nucleic DNA and causes its degradation [37,63]. Klf1 expressed in CMEIs binds and activates the promoter of DnaseII-alpha, which is severely down-regulated in the Klf1 KO mouse foetal liver [37]. ...
... Fundamental to this function is the expression of DnaseII-alpha protein in macrophages, which hydrolyses nucleic DNA and causes its degradation [37,63]. Klf1 expressed in CMEIs binds and activates the promoter of DnaseII-alpha, which is severely down-regulated in the Klf1 KO mouse foetal liver [37]. Accumulation of extruded nuclei in CMEI lysosomes, due to the inability to degrade nucleic DNA, impairs CMEI capacity to sustain erythropoiesis and triggers the production of anti-proliferative cytokines such as interferon-β, which has cytotoxic effects and inhibits erythroid maturation [37,64]. ...
Krüppel-like factor 1 (KLF1) plays a crucial role in erythropoiesis. In-depth studies conducted on mice and humans have highlighted its importance in erythroid lineage commitment, terminal erythropoiesis progression and the switching of globin genes from γ to β. The role of KLF1 in haemoglobin switching is exerted by the direct activation of β-globin gene and by the silencing of γ-globin through activation of BCL11A, an important γ-globin gene repressor. The link between KLF1 and γ-globin silencing identifies this transcription factor as a possible therapeutic target for β-hemoglobinopathies. Moreover, several mutations have been identified in the human genes that are responsible for various benign phenotypes and erythroid disorders. The study of the phenotype associated with each mutation has greatly contributed to the current understanding of the complex role of KLF1 in erythropoiesis. This review will focus on some of the principal functions of KLF1 on erythroid cell commitment and differentiation, spanning from primitive to definitive erythropoiesis. The fundamental role of KLF1 in haemoglobin switching will be also highlighted. Finally, an overview of the principal human mutations and relative phenotypes and disorders will be described.
... 17 The deficiency of the KLF1 is not compatible with life, as the KLF1 KO mice embryos die of severe anemia. The KFL1 was found to bind directly to the DNase II promoter and the KLF1 KO embryos have an extremely reduced DNase II expression, 24 which may explain their phenotype. In addition, studies conducted using the KLF1-GPF mice or inducing the KFL1 in human macrophages in vitro revealed that the KFL1 is responsible for several features of EBI macrophages, such as expression of the VCAM-1, CD163 and CD169, in addition to the DNase II, and enables macrophage to induce the erythroid maturation. ...
Introduction
The development of red blood cells (RBCs), or erythropoiesis, occurs in specialized niches in the bone marrow, called erythroblastic islands, composed of a central macrophage surrounded by erythroblasts at different stages of differentiation.
Hypothesis and Method
Upon anemia or hypoxemia, erythropoiesis extends to extramedullary sites, mainly spleen and liver, a process known as stress erythropoiesis, leading to the expansion of erythroid progenitors, iron recruitment and increased production of reticulocytes and mature RBCs.
Method
Macrophages are key cells in both homeostatic and stress erythropoiesis, providing conditions for erythroid cells to survive, proliferate and differentiate. During RBCs aging and injury, macrophages play a fundamental role again, performing the clearance of these cells and recycling iron for new erythroblasts in development.
Conclusion
Thus, macrophages are crucial components of the RBCs turnover and in this review, we aimed to cover the main known mechanisms involved in the process of birth and death of RBCs, highlighting the importance of macrophage functions in the whole RBC lifecycle.
... This macrophage aids erythroid maturation by providing cytokines and growth factors, enables enucleation by providing phagocytic functions, and ultimately provides an effective means for reticulocyte formation and release (reviewed comprehensively in Chasis and Mohandas (2008), Bieker (2008), de Back et al. (2014), Hom et al. (2015), Klei et al. (2017), Li et al. (2020)). As a result, considerable effort has been dedicated to characterizing EBI macrophages by studying cell surface marker expression for their efficient isolation (Soni et al., 2006;Porcu et al., 2011;Chow et al., 2013;Seu et al., 2017;Li et al., 2019), with various groups reporting different combinations of markers associated with them (Sadahira et al., 1991;Sadahira et al., 1995;Chow et al., 2013;Seu et al., 2017;Li et al., 2019;Yeo et al., 2019b;Mukherjee et al., 2021;Zhang et al., 2021). ...
... Thus, our previous understanding of EKLF's role in erythropoiesis as being restricted to the erythroid compartment required reassessment for which, firstly, EKLF expression in F4/80+ macrophages had to be directly and clearly demonstrated. This was accomplished by purifying F4/80+ macrophages from E14.5 FL and detecting EKLF mRNA expression by RT-PCR and protein expression by immunostaining (Porcu et al., 2011;Mukherjee et al., 2021). Subsequently, using a transgenic mouse expressing GFP under the EKLF promoter (pEKLF/ GFP; (Lohmann and Bieker, 2008)) it was shown that almost 30% of all F4/80+ macrophages from E13.5 FL are GFP+ (and thus likely EKLF+) (Xue et al., 2014). ...
... Earlier studies suggested that EKLF is important for the expression of DNase2a and Vcam1 in EBI macrophages (Porcu et al., 2011;Xue et al., 2014). However, given the severe alterations in EBIs from EKLF −/− mice, and the known global role of EKLF in erythroid cells, it was unlikely that EKLF function in EBI macrophages would be restricted to just these two genes. ...
During definitive erythropoiesis, maturation of erythroid progenitors into enucleated reticulocytes requires the erythroblastic island (EBI) niche comprising a central macrophage attached to differentiating erythroid progenitors. Normally, the macrophage provides a nurturing environment for maturation of erythroid cells. Its critical physiologic importance entails aiding in recovery from anemic insults, such as systemic stress or acquired disease. Considerable interest in characterizing the central macrophage of the island niche led to the identification of putative cell surface markers enriched in island macrophages, enabling isolation and characterization. Recent studies focus on bulk and single cell transcriptomics of the island macrophage during adult steady-state erythropoiesis and embryonic erythropoiesis. They reveal that the island macrophage is a distinct cell type but with widespread cellular heterogeneity, likely suggesting distinct developmental origins and biological function. These studies have also uncovered transcriptional programs that drive gene expression in the island macrophage. Strikingly, the master erythroid regulator EKLF/Klf1 seems to also play a major role in specifying gene expression in island macrophages, including a putative EKLF/Klf1-dependent transcription circuit. Our present review and analysis of mouse single cell genetic patterns suggest novel expression characteristics that will enable a clear enrichment of EBI subtypes and resolution of island macrophage heterogeneity. Specifically, the discovery of markers such as Epor, and specific features for EKLF/Klf1-expressing island macrophages such as Sptb and Add2, or for SpiC-expressing island macrophage such as Timd4, or for Maf/Nr1h3-expressing island macrophage such as Vcam1, opens exciting possibilities for further characterization of these unique macrophage cell types in the context of their critical developmental function.
... Mer tyrosine kinase (MERTK), which binds protein S bound to phosphatidyl serine at the surface of the pyrenocyte, plays an important role in pyrenocyte attachment to the EBI macrophage [29,40,41]. DNAse 2α within EBI macrophages is essential to degrade the DNA within the pyrenocyte nucleus [43,44]. Interestingly, although the presence of pyrenocytes was not stated explicitly, mice and rats with depleted or absent macrophages in the foetal liver do not accumulate obvious nuclear material [45][46][47], suggesting that during foetal haematopoiesis, another cell type may be able to degrade the expelled nucleus. ...
It has recently emerged that tissue resident macrophages are key regulators of several stem cell niches orchestrating tissue formation during development, as well as postnatally where they also organise the repair and regeneration of many tissues including the haemopoietic tissue. The fact that macrophages are also master regulators and effectors of innate immunity and inflammation allows them to co-ordinate haematopoietic response to infections, injuries and inflammation. After recently reviewing the roles of phagocytes and macrophages in regulating normal and pathological haematopoietic stem cell niches, we now focus on the key roles of macrophages in regulating erythropoiesis and iron homeostasis. We review herein the recent advances in understanding how macrophages at the centre of erythroblastic islands form an erythropoietic niche that controls the terminal differentiation and maturation of erythroblasts into reticulocytes, how red pulp macrophages in the spleen control iron recycling and homeostasis, how these macrophages coordinate emergency erythropoiesis in response to blood loss, infections and inflammation and how persistent infections or inflammation can lead to anaemia of inflammation via macrophages. Finally, we discuss the technical challenges associated with the molecular characterisation of erythroid island macrophages and red pulp macrophages.
... Among the factors regulating erythropoiesis is the Erythroid Krüppel-like factor (EKLF/KLF1), a pivotal regulator that functions in erythroid differentiation and fate decision through the bipotential megakaryocyte-erythroid progenitors (MEPs) [6][7][8][9][10], as well as the homeostasis of HSC [11]. Eklf is the first identified member of the KLF family of genes expressed in the erythroid cells, mast cells, and their precursors [12,13], as well as some of the other types of the hematopoietic cells, but at low levels [6,14] (Bio GPS). The critical function of Eklf in erythropoiesis was initially demonstrated through gene abolition studies, with the Eklf-knockout mice (Eklf -/-) displaying severe anemia and dying in utero at around embryonic (E) day 14.5 (E14.5) ...
The erythroid Krüppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to the CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and the promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf−/−) mouse embryos, we identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with the molecular/cellular analysis of the mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL, known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tal gene promoter in combination with the in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates the Tal gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors, which sustains mammalian erythropoiesis.
... Consequently, Dnase2a KO mice exhibited severe anemia and inflammation caused by the improper clearance erythrocytes' nuclei, that ultimately induced lethality at an early stage of mouse development (E17.5) (108,202). In addition, thymic development of T cells was severely impaired in Dnase2a deficient mice due to poor elimination of apoptotic thymocytes and subsequent inflammation (203). ...
Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.
